15. INRに応じた投与量調節
INR 2.0-3.0 <2.0 3.0-3.5 3.6-4.0 >4.0
Warfarin 5-20%増量 5-15%減量 10-15%減量 10-20%減量
± 1日休薬 ± 1日休薬
INR 2.5-3.5 <2.0 2.0-2.4 3.6-4.6 4.7-5.2 >5.2
Warfarin 10-20%増量 5-15%増量 5-15%減量 10-20%減量 10-20%減量
± 1日休薬 ± 1-2日休薬
出血Risk Very High ACCP Guideline
INR<5, 出血無し 上記参照
INR 5-9, 出血無し 1-2日分のWarfarin中止
リスク高ければVit K1 1-2.5mg po
緊急性(+) Vit K1 2-4mg po, 24hr後に再検し, 必要ならばさらに1-2mg po
INR >9, 出血無し Vit K1 を5-10mg po, 24-48hr後に再検
INR>20 or 重篤な出血傾向 Vit K1を10mg IV, FFPは必要に応じて投与, 12hr後に再検
16. Nomogramを用いた調節方法
初期投与量10mg vs 5mgでの比較 (Ann Intern Med 2003;138:714-9)
VTE患者201名のDB-RCT. 全例にLMWHを5d使用し,
Warfarin 10mg vs 5mg startで, INR達成までの時間, 副作用を比較.
Article Warfarin Nomograms
10mg開始群の方が1.4d早くINR達成.
Figure 2. Time to therapeutic international normalized ratio
また, Day 5でのINR達成率は, (INR) in each study group.
83% vs 46%と10mg群でより多い.
INRの過延長は有意差無し.
10mg群では, Day 8に98%が
治療域を達成する
(Pathophysiol Haemost Thromb 2002;32:131-3)
16
22. Table 2. Characteristics of Warfarin Treatment During the Study Ann Intern Med. 2011;155:653-659.
Outcome 4-Week Group 12-Week Group* Absolute Difference (CI), P Value
(n )621 ؍ (n )421 ؍ percentage points
Mean time in study (SD), d 349 (72) 356 (56)
Mean PT tests (SD), n 11.9 (2.5) 12.4 (2.3)
Mean time in therapeutic range (SD), % 74.1 (18.8) 71.6 (20.0) 2.5 (7.3)† 0.020‡
Mean number of INRs in therapeutic range (SD) 8.4 (2.8) 8.4 (2.9)
Patients with extreme INRs, n (%)§
INR Ն4.5 15 (11.9) 8 (6.5)
INR Յ1.5 12 (9.5) 11 (8.9)
Number of extreme INRs, n (%)
0 99 (78.6) 107 (86.3)
1 19 (15.1) 12 (9.7)
2 6 (4.8) 4 (3.2)
3 2 (1.6) 1 (0.8)
Ն1 27 (21.4) 17 (13.7) 7.7 (–1.8 to 17.1) 0.11
Patients with dose changes, n (%)
0 dose changes 56 (44.4) 78 (62.9)
1 dose change 38 (30.2) 19 (15.3)
2 dose changes 13 (10.3) 17 (13.7)
3 dose changes 11 (8.7) 6 (4.8)
Ն4 dose changes 8 (6.3) 4 (3.2)
Ն1 dose change 70 (55.6) 46 (37.1) 18.5 (6.1 to 30.0) 0.004
Clinical events, n (%)
Major bleeding event 1 (0.8) 2 (1.6) –0.8 (–4.9 to 2.9) 0.55
Verified thromboembolic event 1 (0.8) 0 (0) 0.8 (–2.3 to 4.4) 0.32
Death 5 (4.0) 2 (1.6) 2.4 (–2.3 to 7.5) 0.25
INR ϭ international normalized ratio; PT ϭ prothrombin time.
面白いことに, INRが過度に亢進する割合は4wk毎調節群の方が多い.
* 2 of every 3 results in this group were shams.
† One-sided 97.5% upper confidence bound (i.e., noninferiority concluded if Ͻ7.5%).
‡ Test of inferiority vs. noninferiority (margin, 7.5%); all other P values refer to superiority tests.
Dose調節数も当然4wk毎調節群の法が多く,
§ Patients may have Ͼ1 extreme INR.
2-sided 95% CI.
長期的にみるとあまりDoseをいじらない方がINRは安定している.
justed P ϭ 0.020; adjusted P ϭ 0.019 for tests of nonin- General Hospital laboratory; and, with borderline statisti-
出血, 血栓症, 死亡リスクは両者変わらず. cal significance, an INR therapeutic range of 2.0 to 3.0.
feriority). The proportion of patients with at least 1 change
26. Vitamin K1
Vit K1は>10mgで、数日~2W Warfarin効果得られないことがあり,
使用後はヘパリンを併用することを忘れない.
Vitamin KはSCよりPOの方が効果発現が速い PO
6.3 SC
1mg PO vs SCのRCT 4.2
2.0
(Ann Intern Med 2002;137:251-4) Day 1 Day 2 Day 3 Day 4
IVとPOではIVが速い
(Arch Intern Med 2003;163:2469-73)
A; INR 6-10; 0.5mg IV vs 2.5mg PO
B; INR >10; 1mg IV vs 5mg PO
IV投与が速いが,
24hr時点では同等の効果
27. Warfarin内服中の患者でINR 4.5-10.0と延長を認めた724名
(RCT, DB, 90Dフォロー, 追跡98%)(Ann Intern Med 2009;150:293-300)
急性の補正が必要 or 出血(+)の患者は除外される
1日間Warfarin offした後,
Vit K 1.25mg po vs. Placeboで出血リスク, 血栓, 死亡を比較
Outcome @ 7D INRはVit K群で有意に低下.
Outcome Vit K(%) Placebo(%) RD(%) (ΔINR 2.8 vs 1.4)
Any bleeding 7.9[5.3-11.2] 9.2 [6.5-12.6] -1.3 [-5.7~3.0] 出血リスクは有意差認めないが,
Major bleeding ― ― ― 日本人ではINR>2.6で
血栓症 0.3 [0.0-1.6] 0.3 [0.0-1.5] 0.0 [-1.0~1.1] 出血リスク上昇を認めるため,
死亡 0.0 [0.0-1.0] 0.3 [0.0-1.5] 0.3 [-1.1~0.5] INR高値の際は注意は必要.
Outcome @ 30D Outcome @ 90D
Outcome Vit K(%) Placebo(%) RD(%) Vit K(%) Placebo(%) RD(%)
Any bleeding 11.5[8.4-15.3] 12.7[9.5-16.6] -1.2[-6.2~3.8] 15.8[12.1-20.0] 16.3[12.6-20.4] -0.5[-6.1~5.1]
Major bleeding ― ― ― 2.5[1.2-4.8] 1.1[0.3-2.8] 1.5[-0.8~3.7]
血栓症 0.6[0.1-2.0] 0.3[0.0-1.5] 0.3[-0.9~1.5] 1.1[0.3-2.9] 0.8[0.2-2.4] 0.3[-1.4~2.0]
死亡 0.3[0.0-1.6] 1.4[0.4-3.1] -1.1[-2.7~0.5] 2.0[0.8-4.0] 1.9[0.8-3.9] 0.1[-2.2~2.4]
28. The American Journal of Medicine (2011) 124, 527-533
高齢者におけるVit K1の効果
≥75yr, INR≥5.0を満たす239名のCohort.
ACCP guidelineに則りVit K1投与を施行し, 翌日のINRをフォロー.
Baseline INR 6.8±2.4 → 翌日INR 2.7±1.3まで低下.
出血リスク低であるINR 1.8-3.2を達成したのは55%.
INR<1.8は20%, INR>3.2は25%.
INR1.5-4.5となったのは86%.
出血Risk Very High ACCP Guideline
INR<5, 出血無し 上記参照
INR 5-9, 出血無し 1-2日分のWarfarin中止
リスク高ければVit K1 1-2.5mg po
緊急性(+) Vit K1 2-4mg po, 24hr後に再検し, 必要ならばさらに1-2mg po
INR >9, 出血無し Vit K1 を5-10mg po, 24-48hr後に再検
28
INR>20 or 重篤な出血傾向 Vit K1を10mg IV, FFPは必要に応じて投与, 12hr後に再検
29. managed according to recommendations, for 48 values be-
The American Journal of Medicine (2011) 124, 527-533 was
tween 5.0 and 6.0, VKA dose was omitted and vitK1
not administered but the INR was checked on Day 1. In 11 DISCUSSION
INRが過延長する10日前に開始された薬剤
cases, the appropriate vitK1 dose was given but the INR This study is the first to address the management of over-
could not be measured the next day because the patients anticoagulation in very elderly inpatients (n ϭ 239, mean
were discharged from the hospital in the interval. In the
抗生剤, PPIが多く, それら薬剤開始後は要注意
remaining 106 INRs Ն5, the guidelines were not followed
for at least one reason: vitK1 was not administered (n ϭ 51) Table 3 Vitamin K Antagonist-potentiating Drugs Added
despite an INR Ͼ6.0, vitK1 was not administered on Day 0 within 10 days before the Episode of Overanticoagulation
(n ϭ 14), the vitK1 dose was inappropriate (n ϭ 16), or the
Potentiating Drugs n (%)
INR was not checked on Day 1 (n ϭ 79).
In the subgroup of patients for whom INRs were man- Antibiotics 60 (68)
aged with VKA dose omission and vitK1 administration Systemic/topical azole antifungal agents 13 (15)
according to guidelines, without PCC, the mean INR value Proton-pump inhibitors 11 (13)
decreased from 6.8 Ϯ 2.4 (Range: 5.0-20.0) on Day 0 to Amiodarone 7 (8)
2.7 Ϯ 1.3 (Range: 1.1-10.1) on Day 1 (Figure 2) (P Ͻ.0001) Serotonin reuptake inhibitors 4 (5)
Vit K1投与量と,
(n ϭ 217). Of these 217 values, 119 (55%) Day 1 INRs were
Statins 8 (9)
L-thyroxin 2 (2)
in the 1.8-3.2 range; 44 (20%) were Ͻ1.8, 54 (25%) were Colchicine 2 (2)
翌日のINR値の分布
Ͼ3.2; 186 (86%) were in the 1.5-4.5 range, 14 (6%) were Tramadol 1 (1)
Ͻ1.5 (marked overcorrection), and 17 (8%) were Ͼ4.5
Base INRundercorrection).
(marked 5.8±0.7 6.6±1.1 10.1±0.9 13.8±3
翌日のINR/Vit K1 1-1.5mg 2-2.5mg 5mg >5mg 1-1.5mgと2-2.5mg投与群では,
1.8-3.2 57% 50% 56% 36% Baseline, 投与翌日のINRは
>3.2 27% 32% 0 7%
さほど変わらない.
<1.8 16% 18% 45% 57%
1.5-4.5 87% 77% 100% 71%
>4.5 8% 14% 0 0
<1.5 5% 9% 0 29% 29